The endocannabinoid (EC) system represents one of the most important modulatory systems in the brain and is known to impact neurobiological factors implicated in Bipolar Disorder (BD), including dopamine (DA), a neurotransmitter associated with mania and cognitive impairments linked to BD. Impaired inhibition is associated with DA dysfunction and is a cardinal feature of BD that affects every day functioning and quality of life. Potential interaction between DA and other neural systems remains unclear, limiting the understanding of the neurobiology of BD and the development of novel treatments. Attempts to model the neuropathology of BD in animals remains limited by a dearth of comprehensive translational paradigms and ambiguity in the interpretation of rodent behaviors postulated to mirror human symptoms. Further, despite prevalent cannabis use in BD, the function of the EC system has also not been examined in this disorder. This application will examine the role of endocannabinoids in people with BD and their relationship to disinhibition using cross- species measures, including a novel human open-field paradigm (the Human Behavior Pattern Monitor or hBPM). To study the EC system, cerebrospinal fluid (CSF) levels of the two primary endogenous cannabinoids, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), will be compared between euthymic BD subjects and healthy volunteers. We will test the hypothesis that the EC system is chronically dysregulated in BD as indicated by increased AEA and 2-AG. 70 euthymic, non-substance-abusing BD subjects (35 subjects on a mood stabilizer and 35 subjects on a combination of a mood stabilizer and antidepressant) will be compared to 35 subjects without an Axis I disorder. Potential medication effects on EC levels will be examined. In order to examine the relationship between the EC system and putative hyperdopaminergic function in BD, we will assess the association between CSF AEA and CSF homovanillic acid (HVA), the primary DA metabolite in the brain. A secondary aim is to test the hypothesis that lower EC levels, proposed to increase DA transmission, are related to BD disinhibition assessed in the hBPM and other measures such as the 5- Choice Continuous Performance Task. All of the cognitive measures proposed are cross-species in nature, allowing for a future detailed examination of the cognitive deficits seen in BD patients and replicated in animal models. The relationship between CSF HVA and motor activity in BD subjects will also be quantified, enabling confirmation of the role of DA in the disorder and validation of DA-based rodent models of BD. This research will fill a gap in understanding the role of the endocannabinoid system and DA in Bipolar Disorder. Our findings will lay the groundwork for future studies that examine the effects and implications of prevalent cannabis use in BD as well as the potential utility of BD treatments that involve modulation of the EC system. PUBLIC HEALTH RELEVANCE: The endocannabinoid (EC) system is an important brain system which plays a critical role in the regulation of neurotransmitters such as dopamine. Dopamine dysregulation is implicated in the mania and inhibitory deficits associated with Bipolar Disorder (BD), but the relationship between the EC system and dopamine among people with BD has not been well studied. This application will examine the role of the EC system in BD and its association with dopamine as well as the EC system's relationship to disinhibition, and is hoped to lead to better prevention and treatment efforts.